Iron deficiency anaemia is characterised by low levels of iron in the blood and can be due to insufficient dietary intake of iron, or loss of iron from internal bleeding caused by diseases of the gastrointestinal or urinary tract, for example inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. Ulcerative colitis is a chronic inflammatory disease affecting the colon and anaemia is recognised as a serious complication and symptom of ulcerative colitis. Iron deficiency anaemia (IDA) in inflammatory bowel disease (IBD) is primarily caused by chronic blood loss from inflamed mucosa and/or iron malabsorption in both active and inactive stages of the disease (1). Dietary restriction and highly selective diets amongst IBD patients often result in poor dietary intake, whilst mucosal inflammation in the gastrointestinal tract may lead to inadequate nutrient absorption (2). Characteristic symptoms of IDA in IBD include chronic fatigue, headache and impairment of cognitive function.
Iron deficiency, without anaemia, has also been shown to have clinical consequences for patients and individuals. Iron is an important component of many intracellular processes and the effect of iron deficiency or iron deficiency correction has been reported in chronic heart failure, growth, behaviour and learning in children and cognition in the elderly. When iron deficiency remains untreated it can lead to iron deficiency anaemia.
Typically, treatment for iron deficiency anaemia is in the form of ferrous iron (Fe2+) salts, (e.g. ferrous sulphate) dosed orally as 300 mg tablets (60 mg elemental iron) three to four times daily. However, as the duodenum can maximally absorb only 10-20 mg of iron a day, greater than 90% of ingested iron is not absorbed, leading to symptomatic adverse events including toxicity at the gastrointestinal mucosa, abdominal pain, nausea, vomiting, constipation, diarrhoea and dark stools, all of which are dose related and lead to poor adherence with treatment.
In addition if ferrous iron tablets become lodged in the upper gastrointestinal tract contact irritation may occur causing erosion or ulceration. Hence treatment with ferrous iron is badly tolerated leading to poor compliance, particularly in patients suffering from IBD who already have significant damage to their gastrointestinal tract (3-4). In fact, treatment with ferrous iron preparations in such patients can often worsen their condition and lead to treatment of such patients with intravenous iron administration.
Alternative treatment with oral ferric iron (Fe3+) salts also results in poor iron absorption due to the ready formation of insoluble chelates when passing from the acidic environment of the stomach to the small intestine. Consequently there is a need to overcome the above-identified problems associated with current oral treatments for iron deficiency anaemia. There is a particular need to develop new orally-dosed iron-based treatments for patients who are intolerant of ferrous iron compositions.
ST10, also referred to as ferric trimaltol and ferric maltol is a chemically stable complex formed between ferric iron (Fe3+) and maltol (3-hydroxy-2-methyl-4-pyrone) was developed as an alternative to oral ferrous products and has been shown to correct iron deficiency in subjects with a history of ferrous sulphate intolerance (5). ST10 makes iron available in the gastrointestinal tract, providing iron in a biologically labile form for uptake across the mucus layer and intestinal wall (5). Since the iron is stabilized in a chelated form it is less toxic; therefore together with its high bioavailability, lower doses of elemental iron are administered thereby improving toxicity and patient compliance.
Harvey et al (6) reported single doses of 30 mg ST10 twice daily in patients recruited from gastroenterology clinics, those presenting with active inflammatory disease were excluded from the study.
The inventors have found that a combination of a particular dosage regimen and tablet formulation have led to surprising improvement in haemoglobin levels in patients suffering from iron deficiency with or without anaemia and in addition, from anaemia resulting from Crohn's disease or ulcerative colitis, which were previously intolerant to oral ferrous products. These results have been reported as clinically meaningful even after a short treatment period of four weeks and confirm that ST10 is an effective therapy for iron deficiency anaemia in IBD patients and may be administered safely over a twelve week period or longer with reduced side effects and improved compliance. In addition the inventors have observed fewer common side effects associated with ferrous iron treatment such as gut related side effects, reduction in blackened stools and compatibility with antacid treatments.